Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure

Allan R Shepard; Nasreen Jacobson; J Cameron Millar; Iok-Hou Pang; H Thomas Steely; Charles C Searby; Val C Sheffield; Edwin M Stone; Abbot F Clark

doi:10.1093/hmg/ddm001

Back

Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure

Journal article

Open access

Peer reviewed

Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure

Allan R Shepard, Nasreen Jacobson, J Cameron Millar, Iok-Hou Pang, H Thomas Steely, Charles C Searby, Val C Sheffield, Edwin M Stone and Abbot F Clark

Human molecular genetics, Vol.16(6), pp.609-617

03/15/2007

DOI: 10.1093/hmg/ddm001

PMID: 17317787

Files and links (1)

url

https://doi.org/10.1093/hmg/ddm001View

Published (Version of record) Open Access

Abstract

Glaucoma is a leading cause of worldwide irreversible visual impairment and blindness and is a clinically and genetically heterogenous group of optic neuropathies. Specific mutations in the myocilin (MYOC) gene cause primary open angle glaucoma (POAG) with varying age-of-onset and degree of severity. We show a mutation-dependent, gain-of-function association between human myocilin and the peroxisomal targeting signal type 1 receptor (PTS1R). There was correlation between the glaucoma phenotype and the specific MYOC mutations, with the more severe early-onset POAG mutations having a higher degree of association with PTS1R. Expression of human myocilin glaucomatous mutations in mouse eyes causes elevated intraocular pressure, which is a major phenotype of MYOC glaucoma. This is the first demonstration of a disease resulting from mutation-induced exposure of a cryptic signaling site that causes mislocalization of mutant protein to peroxisomes and the first disease-gene-based animal model of human POAG.

Glycoproteins - genetics

Cell Line

Cytoskeletal Proteins - genetics

Glaucoma, Open-Angle - genetics

Intraocular Pressure

Humans

Glaucoma, Open-Angle - physiopathology

Glycoproteins - metabolism

Cercopithecus aethiops

Peroxisomes - metabolism

Animals

Eye Proteins - metabolism

Peroxisome-Targeting Signal 1 Receptor

Cytoskeletal Proteins - metabolism

Glaucoma, Open-Angle - metabolism

Mice

Eye Proteins - genetics

COS Cells

Eye - physiopathology

Receptors, Cytoplasmic and Nuclear - metabolism

Details

Title: Subtitle: Glaucoma-causing myocilin mutants require the Peroxisomal targeting signal-1 receptor (PTS1R) to elevate intraocular pressure
Creators: Allan R Shepard - Glaucoma Research, Alcon Research, Ltd, Fort Worth, TX 76134, USA. allan.shepard@alconlabs.com
Nasreen Jacobson
J Cameron Millar
Iok-Hou Pang
H Thomas Steely
Charles C Searby
Val C Sheffield
Edwin M Stone
Abbot F Clark
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.16(6), pp.609-617
DOI: 10.1093/hmg/ddm001
PMID: 17317787
NLM abbreviation: Hum Mol Genet
ISSN: 0964-6906
eISSN: 1460-2083
Publisher: England
Grant note: R01 EY10564 / NEI NIH HHS
Language: English
Date published: 03/15/2007
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics; Ophthalmology and Visual Sciences
Record Identifier: 9983979975202771

Metrics

30 Record Views

88 Times Cited - Web of Science